Enhancing the accuracy of virtual screening: molecular dynamics with quantum-refined force fields

Summary A methodology aimed at improving the accuracy of current docking–scoring procedures is proposed, and validated through detailed tests of its performance in predicting the activity of HIV-1 protease inhibitors. This methodology is based on molecular dynamics simulations using a force field whose effective charges are refined by means of a novel procedure that relies on quantum-mechanical calculations and preserves the internal consistency of the parameterization scheme.     

Aminoglycoside microarrays to explore interactions of antibiotics with RNAs and proteins

RNA is an important target for drug discovery efforts. Several clinically used aminoglycoside antibiotics bind to bacterial rRNA and inhibit protein synthesis. Aminoglycosides, however, are losing efficacy due to their inherent toxicity and the increase in antibiotic resistance. Targeting of other RNAs is also becoming more attractive thanks to the discovery of new potential RNA drug targets through genome sequencing and biochemical efforts. Identification of new compounds that target RNA is therefore urgent, and we report here on the development of rapid screening methods to probe binding of low molecular weight ligands to proteins and RNAs. A series of aminoglycosides has been immobilized onto glass microscope slides, and binding to proteins and RNAs has been detected by fluorescence. Construction and analysis of the arrays is completed by standard DNA genechip technology. Binding of immobilized aminoglycosides to proteins that are models for study of aminoglycoside toxicity (DNA polymerase and phospholipase C), small RNA oligonucleotide mimics of aminoglycoside binding sites in the ribosome (rRNA A-site mimics), and a large (approximately 400 nucleotide) group I ribozyme RNA is detected. The ability to screen large RNAs alleviates many complications associated with binding experiments that use isolated truncated regions from larger RNAs. These studies lay the foundation for rapid identification of small organic ligands from combinatorial libraries that exhibit strong and selective RNA binding while displaying decreased affinity to toxicity-causing proteins.     

Chemistry in microstructured reactors

The application of microstructured reactors in the chemical process industry has gained significant importance in recent years. Companies that offer not only microstructured reactors, but also entire chemical process plants and services relating to them, are already in existence. In addition, many institutes and universities are active within this field, and process-engineering-oriented reviews and a specialized book are available. Microstructured systems can be applied with particular success in the investigation of highly exothermic and fast reactions. Often the presence of temperature-induced side reactions can be significantly reduced through isothermal operations. Although microstructured reaction techniques have been shown to optimize many synthetic procedures, they have not yet received the attention they deserve in organic chemistry. For this reason, this Review aims to address this by providing an overview of the chemistry in microstructured reactors, grouped into liquid-phase, gas-phase, and gas-liquid reactions.     

A Biokinetic Model to Describe Consequences of Inhibition/Stimulation in <Emphasis Type="Italic">DNA</Emphasis>-Proofreading and -Repair,Part 4

Summary. In previous papers a strongly simplified physical-mathematical (biokinetic) model has been presented, which dealt with the factors influencing the timely development of DNA mismatches dependent cells (malignant cells) in their kinetic competition to the development of normal somatic cells (i.e. cells with correct genetic information). The kinetic results have been studied by comparing them with experimental results reported in the literature upon inhibiting the organisms own enzymatic DNA-proofreading and repair machinery. In spite of the fact that the model uses fully the chances of kinetics, which allows to describe even rather complicated systems with many regulation circuits and feed back loops in a rather simple, summarizing way, it has been demonstrated that the model does not only well describe the experimentally found significant increases of mutants in cases when the DNA repair system has been inhibited, but it can also reflect cancer-development and the efficacy of classical cancer therapies like surgery or chemotherapy as well.In applying the predictions of the model as to the opposite of an inhibition of the DNA repair system, i.e., in testing the results, if the organisms own repair systems were stimulated, the model shows that there could be a chance for a new, adjuvant cancer-therapy if this concept was combined with biochemical facts and clinical findings which are reported in the literature.In continuation of this concept, the predictions of the model have been compared with findings upon cancer-therapies by apoptosis-triggerers like tamoxifen. Further, according to the fact that there exists literature by which it is demonstrated by clinical facts that it is not necessary to use living cells (e.g. from umbilical cords blood or bone-marrow) to achieve surprising therapeutic successes in cancer therapy, but also cell-free human-placenta-extracts (HPEs) can be similarily effective, it has been tried in a first preliminary analytical effort to characterize effector-substances contained therein.Received January 27, 2003; accepted (revised) March 25, 2003 Published online August 18, 2003     

Electrospray ionization tandem mass spectrometry in high-throughput screening of homogeneous catalysts

The frontispiece shows an illustration by John Tenniel and an excerpt from the 1865 edition of Lewis Carroll's "Alice in Wonderland". Because everything in Wonderland runs counter to logic, the Queen of Hearts declares in Alice's trial "Sentence first-verdict afterwards". High-throughput screening of catalysts, as it is conventionally practiced, does "Synthesis first-screening afterwards" which, as is argued in this review, also backwards. Given the particular constraints present in organometallic complexes, it is more efficient to develop a selective synthesis only when it has already been determined that a structure is likely to be better. The consequence is that screening methods must be able to handle ill-defined mixtures. Electrospray ionization tandem mass spectrometry is presented as a technical solution to this problem.